Thienopyridines and benzothiophenes useful as irak4 inhibitors

ABSTRACT

Disclosed are compounds of Formula (I) or a salt or prodrug thereof, wherein: X is CR 4  or N; Y is CR 5  or N; provided that only one of X and Y is N; (R1) is: or; wherein R 1 , R 1a , R 1b , R 1c , R 2 , and R 3  are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.

The present invention generally relates to thienopyridine andbenzothiophene compounds useful as kinase inhibitors, including themodulation of IRAK-4. Provided herein are thienopyridine andbenzothiophene compounds, compositions comprising such compounds, andmethods of their use. The invention further pertains to pharmaceuticalcompositions containing at least one compound according to the inventionthat are useful for the treatment of conditions related to kinasemodulation and methods of inhibiting the activity of kinases, includingIRAK-4 in a mammal.

Toll/IL-1 receptor family members are important regulators ofinflammation and host resistance. The Toll like receptor (TLR) familyrecognizes molecular patterns derived from infectious organismsincluding bacteria, fungi, parasites, and viruses (reviewed in Kawai, T.et al., Nature Immunol., 11:373-384 (2010)). Ligand binding to thereceptor induces dimerization and recruitment of adaptor molecules to aconserved cytoplasmic motif in the receptor termed the Toll/IL-1receptor (TIR) domain. With the exception of TLR3, all TLRs recruit theadaptor molecule MyD88. The IL-1 receptor family also contains acytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewedin Sims, J. E. et al., Nature Rev. Immunol., 10:89-102 (2010)).

Members of the IRAK family of serine/threonine kinases are recruited tothe receptor via interactions with MyD88. The family consists of fourmembers. Several lines of evidence indicate that IRAK4 plays a criticaland non-redundant role in initiating signaling via MyD88 dependent TLRsand IL-1R family members. Structural data confirms that IRAK4 directlyinteracts with MyD88 and subsequently recruits either IRAK1 or IRAK2 tothe receptor complex to facilitate downstream signaling (Lin, S. et al.,Nature, 465:885-890 (2010)). IRAK4 directly phosphorylates IRAK1 tofacilitate downstream signaling to the E3 ubiquitin ligase TRAF6,resulting in activation of the serine/threonine kinase TAK1 withsubsequent activation of the NFκB pathway and MAPK cascade (Flannery, S.et al., Biochem. Pharmacol., 80:1981-1991 (2010)). A subset of humanpatients was identified who lack IRAK4 expression (Picard, C. et al.,Science, 299:2076-2079 (2003)). Cells from these patients fail torespond to all TLR agonists with the exception of TLR3 as well as tomembers of the IL-1 family including IL-1β and IL-18 (Ku, C. et al., J.Exp. Med., 204:2407-2422 (2007)). Deletion of IRAK4 in mice results in asevere block in IL-1, IL-18 and all TLR dependent responses with theexception of TLR3 (Suzuki, N. et al., Nature, 416:750-754 (2002)). Incontrast, deletion of either IRAK1 (Thomas, J. A. et al., J. Immunol.,163:978-984 (1999); Swantek, J. L. et al., J. Immunol., 164:4301-4306(2000) or IRAK2 (Wan, Y. et al., J. Biol. Chem., 284:10367-10375 (2009))results in partial loss of signaling. Furthermore, IRAK4 is the onlymember of the IRAK family whose kinase activity has been shown to berequired for initiation of signaling. Replacement of wild type IRAK4 inthe mouse genome with a kinase inactive mutant (KDKI) impairs signalingvia all MyD88 dependent receptors including IL-1, IL-18 and all TLRswith the exception of TLR3 (Koziczak-Holbro, M. et al., J. Biol. Chem.,282:13552-13560 (2007); Kawagoe, T. et al., J. Exp. Med., 204:1013-1024(2007); and Fraczek, J. et al., J. Biol. Chem., 283:31697-31705 (2008)).

As compared to wild type animals, IRAK4 KDKI mice show greatly reduceddisease severity in mouse models of multiple sclerosis (Staschke, K. A.et al., J. Immunol., 183:568-577 (2009)), rheumatoid arthritis(Koziczak-Holbro, M. et al., Arthritis Rheum., 60:1661-1671 (2009)),atherosclerosis (Kim, T. W. et al., J. Immunol., 186:2871-2880 (2011)and Rekhter, M. et al., Biochem. Biophys. Res. Comm., 367:642-648(2008)), and myocardial infarction (Maekawa, Y. et al., Circulation,120:1401-1414 (2009)). As described, IRAK4 inhibitors will block allMyD88 dependent signaling. MyD88 dependent TLRs have been shown tocontribute to the pathogenesis of multiple sclerosis, rheumatoidarthritis, cardiovascular disease, metabolic syndrome, sepsis, systemiclupus erythematosus, inflammatory bowel diseases including Crohn'sdisease and ulcerative colitis, autoimmune uveitis, asthma, allergy,type I diabetes, and allograft rejection (Keogh, B. et al., TrendsPharmacol. Sci., 32:435-442 (2011); Mann, D. L., Circ. Res.,108:1133-1145 (2011); Horton, C. G. et al., Mediators Inflamm., ArticleID 498980 (2010), doi:10.1155/2010/498980; Goldstein, D. R. et al., J.Heart Lung Transplant., 24:1721-1729 (2005); and Cario, E., Inflamm.Bowel Dis., 16:1583-1597 (2010)). Oncogenically active MyD88 mutationsin diffuse large B cell lymphomas have been identified that aresensitive to IRAK4 inhibition (Ngo, V. N. et al., Nature, 470:115-121(2011)). Whole genome sequencing also identified mutations in MyD88associated with chronic lymphatic leukemia suggesting that IRAK4inhibitors may also have utility in treating leukemia (Puente, X. S. etal., Nature, 475:101-105 (2011)).

In addition to blocking TLR signaling, IRAK4 inhibitors will also blocksignaling by members of the IL-1 family. Neutralization of IL-1 has beenshown to be efficacious in multiple diseases including gout; goutyarthritis; type 2 diabetes; auto-inflammatory diseases includingCryopyrin-Associated Periodic Syndromes (CAPS), TNF Receptor AssociatedPeriodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), adultonset stills; systemic onset juvenile idiopathic arthritis; stroke;Graft-versus-Host Disease (GVHD); smoldering multiple myeloma; recurrentpericarditis; osteoarthritis; emphysema (Dinarello, C. A., Eur. J.Immunol., 41:1203-1217 (2011) and Couillin, I. et al., J. Immunol.,183:8195-8202 (2009)). In a mouse model of Alzheimer's disease, blockadeof IL-1 receptor improved cognitive defects, attenuated tau pathologyand reduced oligomeric forms of amyloid-β (Kitazawa, M. et al., J.Immunol., 187:6539-6549 (2011)). IL-1 has also been shown to be acritical link to adaptive immunity, driving differentiation of the TH17effector T cell subset (Chung, Y. et al., Immunity, 30:576-587 (2009)).Therefore, IRAK4 inhibitors are predicted to have efficacy in TH17associated diseases including multiple sclerosis, psoriasis,inflammatory bowel diseases, autoimmune uveitis, and rheumatoidarthritis (Wilke, C. M. et al., Trends Immunol., 32:603-661 (2011)).

WO2013/106612, WO2013/106614, WO2013/106641, WO2014/074657, andWO2014/074675 disclose substituted pyridyl compounds useful as kinaseinhibitors, including the modulation of IRAK4.

In view of the conditions that may benefit by treatment involvingmodulation of protein kinases, it is immediately apparent that newcompounds capable of modulating protein kinases such as IRAK-4 andmethods of using these compounds could provide substantial therapeuticbenefits to a wide variety of patients.

The present invention relates to a new class of thienopyridines andbenzothiophene substituted compounds found to be effective inhibitors ofprotein kinases including IRAK-4. These compounds are provided to beuseful as pharmaceuticals with desirable stability, bioavailability,therapeutic index, and toxicity values that are important to theirdrugability.

SUMMARY OF THE INVENTION

The present invention provides to compounds of Formula (I) that areuseful as inhibitors of IRAK-4, and are useful for the treatment ofproliferative diseases, allergic diseases, autoimmune diseases andinflammatory diseases, or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates or prodrugs thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for inhibition of IRAK-4comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for treating proliferative,metabolic, allergic, autoimmune and inflammatory diseases, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof.

One embodiment provides a method for treating inflammatory andautoimmune diseases wherein the treatment of inflammatory diseases iseven more preferred. Particular, inflammatory and autoimmune diseasesinclude, but are not limited to, Crohn's disease, ulcerative colitis,asthma, graft versus host disease, allograft rejection, chronicobstructive pulmonary disease, Graves' disease, rheumatoid arthritis,systemic lupus erythematosus, lupus nephritis, cutaneous lupus,psoriasis, cryopyrin-associated periodic syndromes (CAPS), TNF receptorassociated periodic syndrome (TRAPS), familial Mediterranean fever(FMF), adult onset stills, systemic onset juvenile idiopathic arthritis,multiple sclerosis, neuropathic pain, gout, and gouty arthritis.

One embodiment provides a method for treating gout and gouty arthritis.

An alternate preferred embodiment is a method for treating metabolicdiseases, including type 2 diabetes and atherosclerosis.

One embodiment provides a method for treating cancer comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for the manufacture ofa medicament for the treatment of cancer.

The present invention also provides a compound of Formula (I) or apharmaceutical composition in a kit with instructions for using thecompound or composition.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

These and other features of the invention will be set forth in theexpanded form as the disclosure continues.

DETAILED DESCRIPTION

The first aspect of the present invention provides at least one compoundof Formula (I):

or a salt or prodrug thereof, wherein:

-   X is CR₄ or N;-   Y is CR₅ or N; provided that only one of X and Y is N;-   R₁ is:

-   each R_(1a) is independently H, —OH, F, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆ cycloalkyl; or    two R_(1a) along with the carbon atom to which they are attached,    can form a 3- to 4-membered spirocycloalkyl ring;-   each R_(1b) is independently H, —OH, F, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆ cycloalkyl; or    two R_(1b) along with the carbon atom to which they are attached,    can form a 3- to 4-membered spirocycloalkyl ring;-   each R_(1c) is independently H, —OH, F, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆ cycloalkyl; or    two R_(1c) along with the carbon atom to which they are attached,    can form a 3- to 4-membered spirocycloalkyl ring;-   R_(1a) and R_(1b) along with the carbon atoms to which they are    attached, can form a 3- to 4-membered cycloalkyl ring;-   R_(1b) and R_(1c) along with the carbon atoms to which they are    attached, can form a 3- to 4-membered cycloalkyl ring;-   R₂ is H, halo, C₁₋₃ alkyl, or C₃₋₆ cycloalkyl;-   R₃ is C₁₋₄ alkoxy, C₁₋₄ fluoroalkoxy, or C₃₋₆ cycloalkoxy;-   R₄ is H, halo, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆ cycloalkyl; and-   R₅ is H, halo, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆ cycloalkyl.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein X is CR₄; Y is CR₅; and R₁, R₂, R₃, R₄, andR₅ are defined in the first aspect. Compounds of this embodiment havethe structure of Formula (II):

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein X is N; Y is CR₅; and R₁, R₂, R₃, and R₅ aredefined in the first aspect.

Compounds of this embodiment have the structure of Formula (III):

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein X is CR₄; Y is N; and R₁, R₂, R₃, and R₄ aredefined in the first aspect. Compounds of this embodiment have thestructure of Formula (IV):

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein R₁ is:

and X, Y, R₂, R₃, R_(1a), and R_(1b) are defined in the first aspect.Included in this embodiment are compounds in which R₁ is

Also included in this embodiment are compounds in which R₁ is

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein R₁ is:

and X, Y, R₂, R₃, R_(1a), R_(1b), and R_(1c) are defined in the firstaspect. Included in this embodiment are compounds in which R₁ is

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein R₁ is:

and X, Y, R_(1a), R_(1b), R_(1c), R₂, R₃, R₄, and R₅ are defined in thefirst aspect. Included in this embodiment are compounds in which eachR_(1a) is independently H or C₁₋₂ alkyl; each R_(1b) is independently H,F, —CH₃, —CHF₂, or cyclopropyl; and each R_(1c) is H.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein each R_(1a) is independently H, —OH, F, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆cycloalkyl; and X, Y, R₁, R₂, and R₃ are defined in the first aspect.Included in this embodiment are compounds in which each R_(1a) isindependently H, —OH, F, C₁₋₃ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ alkoxy, C₁₋₂fluoroalkoxy, or C₃₋₆ cycloalkyl. Also included in this embodiment arecompounds in which each R_(1a) is independently H or C₁₋₂ alkyl; andcompounds in which one R_(1a) is H, and the other R_(1a) is —OH, F, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆cycloalkyl.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein two R_(1a) along with the carbon atom towhich they are attached, form a 3- to 4-membered spirocycloalkyl ring;and X, Y, R₁, R₂, and R₃ are defined in the first aspect. Included inthis embodiment are compounds in which two R_(1a) along with the carbonatom to which they are attached, form a 3-membered spirocycloalkyl ring.Also included in this embodiment are compounds in which two R_(1a) alongwith the carbon atom to which they are attached, form a 4-memberedspirocycloalkyl ring.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein each R_(1b) is independently H, —OH, F, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆cycloalkyl; and X, Y, R₁, R₂, and R₃ are defined in the first aspect.Included in this embodiment are compounds in which each R_(1b) isindependently H, —OH, F, C₁₋₃ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ alkoxy, C₁₋₂fluoroalkoxy, or C₃₋₆ cycloalkyl. Also included in this embodiment arecompounds in which each R_(1b) is independently H, F, —CH₃, —CHF₂, orcyclopropyl; and compounds in which one R_(1b) is H, and the otherR_(1b) is F, —CH₃, —CHF₂, or cyclopropyl. Additionally, included in thisembodiment are compounds in which each R_(1b) is H; each R_(1b) is F;and compounds in which each R_(1b) is —CH₃.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein two R_(1b) along with the carbon atom towhich they are attached, form a 3- to 4-membered spirocycloalkyl ring;and X, Y, R₁, R₂, and R₃ are defined in the first aspect. Included inthis embodiment are compounds in which two R_(1b) along with the carbonatom to which they are attached, form a 3-membered spirocycloalkyl ring.Also included in this embodiment are compounds in which two R_(1b) alongwith the carbon atom to which they are attached, form a 4-memberedspirocycloalkyl ring.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein R₁ is:

each R_(1c) is independently H, —OH, F, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆ cycloalkyl; and X, Y, R₂, and R₃are defined in the first aspect. Included in this embodiment arecompounds in which each R_(1c) is independently H, —OH, F, C₁₋₃ alkyl,C₁₋₂ fluoroalkyl, C₁₋₂ alkoxy, C₁₋₂ fluoroalkoxy, or C₃₋₆ cycloalkyl.Also included in this embodiment are compounds in which each R_(1c) isindependently H or C₁₋₂ alkyl; and compounds in which each R_(1c) is H.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein R₁ is:

two R_(1c) along with the carbon atom to which they are attached, form a3- to 4-membered spirocycloalkyl ring; and X, Y, R_(1a), R_(1b), R₂, andR₃ are defined in the first aspect. Included in this embodiment arecompounds in which two R_(1c) along with the carbon atom to which theyare attached, form a 3-membered spirocycloalkyl ring. Also included inthis embodiment are compounds in which two R_(1c) along with the carbonatom to which they are attached, form a 4-membered spirocycloalkyl ring.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein R_(1a) and R_(1b) along with the carbonatoms to which they are attached, form a 3- to 4-membered cycloalkylring; each R_(1b) is independently H, OH, F, C₁₋₃ alkyl, C₁₋₃fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆ cycloalkyl; and X,Y, R₁, R₂, and R₃ are defined in the first aspect. Included in thisembodiment are compounds in which R_(1a) and R_(1b) along with thecarbon atoms to which they are attached, form a 3-membered cycloalkylring. Also, included in this embodiment are compounds in which R_(1a)and R_(1b) along with the carbon atoms to which they are attached, forma 4-membered cycloalkyl ring.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein R₁ is:

each R_(1a) is independently H, OH, F, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆ cycloalkyl; R_(1c) and R_(1c)along with the carbon atoms to which they are attached, form a 3- to4-membered cycloalkyl ring; and X, Y, R₂, and R₃ are defined in thefirst aspect. Included in this embodiment are compounds in which R_(1b)and R_(1c) along with the carbon atoms to which they are attached, forma 3-membered cycloalkyl ring. Also, included in this embodiment arecompounds in which R_(1b) and R_(1c) along with the carbon atoms towhich they are attached, form a 4-membered cycloalkyl ring.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein R₃ is C₁₋₃ alkoxy, C₁₋₂ fluoroalkoxy, orC₃₋₆ cycloalkoxy; and X, Y, R₁, R₂, R₄, and R₅ are defined in the firstaspect. Included in this embodiment are compounds in which R₃ is C₁₋₃alkoxy and C₃₋₆ cycloalkoxy. Also included in this embodiment arecompounds in which R₃ is —OCH₃, —OCH(CH₃)₂, or —O(cyclopropyl).

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein X is CR₄; R₄ is H, halo, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, or C₃₋₆ cycloalkyl; and Y, R₁, R₂, R₃, and R₅ are definedin the first aspect. Included in this embodiment are compounds in whichR₄ is H, F, C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, or C₃₋₆ cycloalkyl. Alsoincluded in this embodiment are compounds in which R₄ is H, F, —CH₃, or—CF₃; and compounds in which R₄ is H.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein Y is CR₅; R₅ is H, halo, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, or C₃₋₆ cycloalkyl; and Y, R₁, R₂, R₃, and R₄ are definedin the first aspect. Included in this embodiment are compounds in whichR₅ is H, F, C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, or C₃₋₆ cycloalkyl. Alsoincluded in this embodiment are compounds in which R₅ is H, F, —CH₃, or—CF₃; and compounds in which R₅ is H.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein each R_(1a) is independently H, —OH, F, C₁₋₃alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ alkoxy, C₁₋₂ fluoroalkoxy, or C₃₋₆cycloalkyl; or two R_(1a) along with the carbon atom to which they areattached, can form a 3- to 4-membered spirocycloalkyl ring; each R_(1b)is independently H, —OH, F, C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ alkoxy,C₁₋₂ fluoroalkoxy, or C₃₋₆ cycloalkyl; or two R_(1b) along with thecarbon atom to which they are attached, can form a 3- to 4-memberedspirocycloalkyl ring; each R_(1c) is independently H, F, C₁₋₂ alkyl,C₁₋₂ fluoroalkyl, or C₃₋₆ cycloalkyl; or two R_(1c) along with thecarbon atom to which they are attached, can form a 3- to 4-memberedspirocycloalkyl ring; R₂ is H, F, Cl, C₁₋₂ alkyl, or C₃₋₆ cycloalkyl; R₃is C₁₋₃ alkoxy, C₁₋₂ fluoroalkoxy, or C₃₋₆ cycloalkoxy; R₄ is H, halo,C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆ cycloalkyl; R₅ is H, halo, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆ cycloalkyl; and X, Y, and R₁ aredefined in the first aspect. Included in this embodiment are compoundsin which X is CH. Also included in this embodiment are compounds inwhich X is CH; and Y is N.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein each R_(1a) is independently H or C₁₋₂alkyl; each R_(1b) is independently H, F, —CH₃, —CHF₂, or cyclopropyl;or two R_(1b) along with the carbon atom to which they are attached, canform a 3-membered spirocycloalkyl ring; each R_(1c) is H; R₂ is H or—CH₃; R₃ is —OCH₃, —OCH(CH₃)₂, or —O(cyclopropyl); R₄ is H; R₅ is H; andX, Y, and R₁ are defined in the first aspect. Included in thisembodiment are compounds in which X is CH. Also included in thisembodiment are compounds in which X is CH; and Y is N.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein each R_(1a) is independently H or C₁₋₂alkyl; each R_(1b) is independently H, F, —CH₃, —CHF₂, or cyclopropyl;or two R_(1b) along with the carbon atom to which they are attached forma 3-membered spirocycloalkyl ring; and X, Y, R₁, R₂, R₃, R₄, and R₅ aredefined in the first aspect. Included in this embodiment are compoundsin which X is CH. Also included in this embodiment are compounds inwhich X is CH; and Y is N.

In one embodiment, a compound of Formula (I) or a salt or a prodrugthereof is provided wherein X is CH; Y is N; R₁ is:

and R_(1a), R_(1b), R₂, R₃, R₄, R₅ are defined in the first aspect.Included in this embodiment are compounds in which R₄ is H; and R₅ is H.Also included are compounds in which one R_(1a) is H and the otherR_(1a) is H or C₁₋₂ alkyl.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein said compound is selected from:3-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide (1);3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(2);(S)-5-methoxy-3-((5-oxopyrrolidin-2-yl)methoxy)thieno[2,3-b]pyridine-6-carboxamide(3);3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxybenzo[b]thiophene-6-carboxamide(4); (S)-5-methoxy-3-((5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide (5);3-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(6);5-methoxy-3-((5-oxomorpholin-3-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(7);3-(((2S,3S,4R)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(8);3-(46S,7R)-7-ethyl-4-oxo-5-azaspiro[2.4]heptan-6-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(9);3-(((2S,3R)-3-ethyl-4,4-dimethyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(10);3-(((2S,4R)-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(11);3-(((2S,3R)-3-(difluoromethyl)-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(12);5-methoxy-3-(((2S)-4-methyl-5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(13-14);3-(((2S)-4-ethyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(15-16);5-methoxy-3-(((2S,3R)-3-methyl-5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(17);3-(((2S,3S,4R)-3-cyclopropyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(18);3-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxy-2-methylthieno[3,2-b]pyridine-6-carboxamide(19);5-cyclopropoxy-3-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(20); 3-(((2S,3S)-4,4-difluoro-3-methyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide (21);3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxy-2-methylthieno[3,2-b]pyridine-6-carboxamide(22);3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-isopropoxythieno[3,2-b]pyridine-6-carboxamide(23);5-cyclopropoxy-3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(24);(S)-5-methoxy-2-methyl-3-((5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(25);3-(((4R,5S)-5-ethyl-2-oxooxazolidin-4-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(26);3-(((2S,3S,4R)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(27);3-(((2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(28); and3-(42S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxybenzo[b]thiophene-6-carboxamide(29).

One embodiment provides compounds of the Formula (I) having IRAK4 IC₅₀values of ≤0.6 μM.

One embodiment provides compounds of the Formula (I) having IRAK4 IC₅₀values of ≤0.1 μM.

One embodiment provides compounds of the Formula (I) having IRAK4 IC₅₀values of ≤0.05 μM.

One embodiment provides compounds of the Formula (I) having IRAK4 IC₅₀values of ≤0.025 μM.

One embodiment provides compounds of the Formula (I) having IRAK4 IC₅₀values of ≤0.015 μM.

One embodiment provides compounds of the Formula (I) having IRAK4 IC₅₀values of ≤0.01 μM.

Definitions

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. Embodiments identified herein as exemplary or preferred areintended to be illustrative and not limiting.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

As used herein, the phase “compounds” refers to at least one compound.For example, a compound of Formula (I) includes a compound of Formula(I) and two or more compounds of Formula (I).

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Listed below are definitions of various terms used to describe thepresent invention. These definitions apply to the terms as they are usedthroughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, andI.

The term “cyano” refers to the group —CN.

The term “amino” refers to the group —NH₂.

The term “oxo” refers to the group ═O.

The term “alkyl” as used herein, refers to both branched andstraight-chain saturated aliphatic hydrocarbon groups containing, forexample, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1to 4 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl(e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscriptafter the symbol “C”, the subscript defines with more specificity thenumber of carbon atoms that a particular group may contain. For example,“C₁₋₆ alkyl” denotes straight and branched chain alkyl groups with oneto six carbon atoms.

The term “fluoroalkyl” as used herein is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupssubstituted with one or more fluorine atoms. For example, “C₁₋₄fluoroalkyl” is intended to include C₁, C₂, C₃, and C₄ alkyl groupssubstituted with one or more fluorine atoms. Representative examples offluoroalkyl groups include, but are not limited to, —CF₃ and —CH₂CF₃.

The term “cycloalkyl,” as used herein, refers to a group derived from anon-aromatic monocyclic or polycyclic hydrocarbon molecule by removal ofone hydrogen atom from a saturated ring carbon atom. Representativeexamples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in asubscript after the symbol “C”, the subscript defines with morespecificity the number of carbon atoms that a particular cycloalkylgroup may contain. For example, “C₃₋₆ cycloalkyl” denotes cycloalkylgroups with three to six carbon atoms. The term “alkoxy,” as usedherein, refers to an alkyl group attached to the parent molecular moietythrough an oxygen atom, for example, methoxy group (—OCH₃). For example,“C₁₋₃ alkoxy” denotes alkoxy groups with one to three carbon atoms.

The terms “fluoroalkoxy” and “—O(fluoroalkyl)” represent a fluoroalkylgroup as defined above attached through an oxygen linkage (—O—). Forexample, “C₁₋₄ fluoroalkoxy” is intended to include C₁, C₂, C₃, and C₄fluoroalkoxy groups.

The term “spirocycloalkyl” refers to a carbocyclyl ring attached to themolecular moiety by a carbon atom in the cycloalkyl ring that is sharedwith the molecular moiety.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of Formula (I) can be provided as amorphous solids orcrystalline solids. Lyophilization can be employed to provide thecompounds of Formula (I) as amorphous solids.

It should further be understood that solvates (e.g., hydrates) of thecompounds of Formula (I) are also within the scope of the presentinvention. The term “solvate” means a physical association of a compoundof Formula (I) with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, ethanolates, methanolates, isopropanolates, acetonitrilesolvates, and ethyl acetate solvates. Methods of solvation are known inthe art.

Various forms of prodrugs are well known in the art and are describedin:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch31, (Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson andH. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers,1991); and

d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and JoachimM. Mayer, (Wiley-VCH, 2003).

In addition, compounds of Formula (I), subsequent to their preparation,can be isolated and purified to obtain a composition containing anamount by weight equal to or greater than 99% of a compound of Formula(I) (“substantially pure”), which is then used or formulated asdescribed herein. Such “substantially pure” compounds of Formula (I) arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to act as aninhibitor to IRAK4; or effective to treat or prevent autoimmune and/orinflammatory disease states, such as multiple sclerosis and rheumatoidarthritis; or effective to treat cancer.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

The compounds of the present invention are intended to include allisotopes of atoms occurring in the present compounds. Isotopes includethose atoms having the same atomic number but different mass numbers. Byway of general example and without limitation, isotopes of hydrogeninclude deuterium (D) and tritium (T). Isotopes of carbon include ¹³Cand ¹⁴C. Isotopically-labeled compounds of the invention can generallybe prepared by conventional techniques known to those skilled in the artor by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed. For example, methyl (—CH₃) also includesdeuterated methyl groups such as —CD₃.

UTILITY

The compounds of the invention modulate kinase activity, including themodulation of IRAK-4. Other types of kinase activity that may bemodulated by the compounds of the instant invention include, but are notlimited to, the Pelle/IRAK family and mutants thereof.

Accordingly, compounds of Formula (I) have utility in treatingconditions associated with the modulation of kinase activity, andparticularly the selective inhibition of IRAK-4 activity or theinhibition of IRAK and other Pelle family kinases. Such conditionsinclude TLR/IL-1 family receptor associated diseases in which cytokinelevels are modulated as a consequence of intracellular signaling.Moreover, the compounds of Formula (I) have advantageous selectivity forIRAK-4 activity, preferably from at least 20 fold to over 1,000 foldmore selective.

As used herein, the terms “treating” or “treatment” encompass thetreatment of a disease state in a mammal, particularly in a human, andinclude: (a) preventing or delaying the occurrence of the disease statein a mammal, in particular, when such mammal is predisposed to thedisease state but has not yet been diagnosed as having it; (b)inhibiting the disease state, i.e., arresting its development; and/or(c) achieving a full or partial reduction of the symptoms or diseasestate, and/or alleviating, ameliorating, lessening, or curing thedisease or disorder and/or its symptoms.

In view of their activity as selective inhibitors IRAK-4, compounds ofFormula (I) are useful in treating TLR/IL-1 family receptor associateddiseases, but not limited to, inflammatory diseases such as Crohn'sdisease, ulcerative colitis, asthma, graft versus host disease,allograft rejection, chronic obstructive pulmonary disease; autoimmunediseases such as Graves' disease, rheumatoid arthritis, systemic lupuserythematosus, psoriasis; auto-inflammatory diseases including CAPS,TRAPS, FMF, adult onset stills, systemic onset juvenile idiopathicarthritis, gout, gouty arthritis; metabolic diseases including type 2diabetes, atherosclerosis, myocardial infarction; destructive bonedisorders such as bone resorption disease, osteoarthritis, osteoporosis,multiple myeloma-related bone disorder; proliferative disorders such asacute myelogenous leukemia, chronic myelogenous leukemia; angiogenicdisorders such as angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; infectious diseases suchas sepsis, septic shock, and Shigellosis; neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, cerebral ischemias orneurodegenerative disease caused by traumatic injury, oncologic andviral diseases such as metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, and HIV infection and CMV retinitis, AIDS, respectively.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoidosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, keloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hypoxia, vascular hyperplasia, cardiac and renalreperfusion injury, thrombosis, cardiac hypertrophy, thrombin-inducedplatelet aggregation, endotoxemia and/or toxic shock syndrome,conditions associated with prostaglandin endoperoxidase syndase-2, andpemphigus vulgaris. Preferred methods of treatment are those wherein thecondition is selected from Crohn's disease, ulcerative colitis,allograft rejection, rheumatoid arthritis, psoriasis, ankylosingspondylitis, psoriatic arthritis, and pemphigus vulgaris. Alternativelypreferred methods of treatment are those wherein the condition isselected from ischemia reperfusion injury, including cerebral ischemiareperfusions injury arising from stroke and cardiac ischemia reperfusioninjury arising from myocardial infarction. Another preferred method oftreatment is one in which the condition is multiple myeloma.

In one embodiment, the compounds of Formula (I) are useful in treatingcancer, including Waldenstrom's Macroglobulinemia (WM), diffuse large Bcell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneousdiffuse large B cell lymphoma, and primary CNS lymphoma.

In addition, the kinase inhibitors of the present invention inhibit theexpression of inducible pro-inflammatory proteins such as prostaglandinendoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2(COX-2), IL-1, IL-6, IL-18, chemokines. Accordingly, additionalIRAK-4-associated conditions include edema, analgesia, fever and pain,such as neuromuscular pain, headache, pain caused by cancer, dental painand arthritis pain. The inventive compounds also may be used to treatveterinary viral infections, such as lentivirus infections, including,but not limited to equine infectious anemia virus; or retrovirusinfections, including feline immunodeficiency virus, bovineimmunodeficiency virus, and canine immunodeficiency virus.

When the terms “IRAK-4-associated condition” or “IRAK-4-associateddisease or disorder” are used herein, each is intended to encompass allof the conditions identified above as if repeated at length, as well asany other condition that is affected by IRAK-4 kinase activity.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof atherapeutically-effective amount of at least one compound of Formula (I)or a salt thereof “Therapeutically effective amount” is intended toinclude an amount of a compound of the present invention that iseffective when administered alone or in combination to inhibit IRAK-4and/or treat diseases.

The methods of treating IRAK-4 kinase-associated conditions may compriseadministering compounds of Formula (I) alone or in combination with eachother and/or other suitable therapeutic agents useful in treating suchconditions. Accordingly, “therapeutically effective amount” is alsointended to include an amount of the combination of compounds claimedthat is effective to inhibit IRAK-4 and/or treat diseases associatedwith IRAK-4.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide,and other immunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; antiviral agents such as abacavir; antiproliferativeagents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®);anti-malarials such as hydroxychloroquine; cytotoxic drugs such asazathiprine and cyclophosphamide; TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus orRAPAMUNE®) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating IRAK-4kinase-associated conditions, including TLR and IL-1 family receptormediated diseases as described above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula (I) and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th Edition (1985), which is incorporated herein by referencein its entirety.

Compounds in accordance with Formula (I) can be administered by anymeans suitable for the condition to be treated, which can depend on theneed for site-specific treatment or quantity of Formula (I) compound tobe delivered.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising a compound of Formula (I) and one or morenon-toxic, pharmaceutically-acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) and,if desired, other active ingredients. The compounds of Formula (I) maybe administered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, or parentally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly, and intrasternallyin dosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. For example, thepharmaceutical carrier may contain a mixture of mannitol or lactose andmicrocrystalline cellulose. The mixture may contain additionalcomponents such as a lubricating agent, e.g. magnesium stearate and adisintegrating agent such as crospovidone. The carrier mixture may befilled into a gelatin capsule or compressed as a tablet. Thepharmaceutical composition may be administered as an oral dosage form oran infusion, for example.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, liquid capsule, suspension, orliquid. The pharmaceutical composition is preferably made in the form ofa dosage unit containing a particular amount of the active ingredient.For example, the pharmaceutical composition may be provided as a tabletor capsule comprising an amount of active ingredient in the range offrom about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, andmore preferably from about 0.5 to 100 mg. A suitable daily dose for ahuman or other mammal may vary widely depending on the condition of thepatient and other factors, but, can be determined using routine methods.

Any pharmaceutical composition contemplated herein can, for example, bedelivered orally via any acceptable and suitable oral preparations.Exemplary oral preparations, include, but are not limited to, forexample, tablets, troches, lozenges, aqueous and oily suspensions,dispersible powders or granules, emulsions, hard and soft capsules,liquid capsules, syrups, and elixirs. Pharmaceutical compositionsintended for oral administration can be prepared according to anymethods known in the art for manufacturing pharmaceutical compositionsintended for oral administration. In order to provide pharmaceuticallypalatable preparations, a pharmaceutical composition in accordance withthe invention can contain at least one agent selected from sweeteningagents, flavoring agents, coloring agents, demulcents, antioxidants, andpreserving agents.

A tablet can, for example, be prepared by admixing at least one compoundof Formula (I) with at least one non-toxic pharmaceutically acceptableexcipient suitable for the manufacture of tablets. Exemplary excipientsinclude, but are not limited to, for example, inert diluents, such as,for example, calcium carbonate, sodium carbonate, lactose, calciumphosphate, and sodium phosphate; granulating and disintegrating agents,such as, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, and alginic acid; binding agents, such as,for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; andlubricating agents, such as, for example, magnesium stearate, stearicacid, and talc. Additionally, a tablet can either be uncoated, or coatedby known techniques to either mask the bad taste of an unpleasanttasting drug, or delay disintegration and absorption of the activeingredient in the gastrointestinal tract thereby sustaining the effectsof the active ingredient for a longer period. Exemplary water solubletaste masking materials, include, but are not limited to,hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplarytime delay materials, include, but are not limited to, ethyl celluloseand cellulose acetate butyrate.

Hard gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one inert solid diluent, suchas, for example, calcium carbonate; calcium phosphate; and kaolin.

Soft gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one water soluble carrier,such as, for example, polyethylene glycol; and at least one oil medium,such as, for example, peanut oil, liquid paraffin, and olive oil.

An aqueous suspension can be prepared, for example, by admixing at leastone compound of Formula (I) with at least one excipient suitable for themanufacture of an aqueous suspension. Exemplary excipients suitable forthe manufacture of an aqueous suspension, include, but are not limitedto, for example, suspending agents, such as, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth,and gum acacia; dispersing or wetting agents, such as, for example, anaturally-occurring phosphatide, e.g., lecithin; condensation productsof alkylene oxide with fatty acids, such as, for example,polyoxyethylene stearate; condensation products of ethylene oxide withlong chain aliphatic alcohols, such as, for exampleheptadecaethylene-oxycetanol; condensation products of ethylene oxidewith partial esters derived from fatty acids and hexitol, such as, forexample, polyoxyethylene sorbitol monooleate; and condensation productsof ethylene oxide with partial esters derived from fatty acids andhexitol anhydrides, such as, for example, polyethylene sorbitanmonooleate. An aqueous suspension can also contain at least onepreservative, such as, for example, ethyl and n-propylp-hydroxybenzoate; at least one coloring agent; at least one flavoringagent; and/or at least one sweetening agent, including but not limitedto, for example, sucrose, saccharin, and aspartame.

Oily suspensions can, for example, be prepared by suspending at leastone compound of Formula (I) in either a vegetable oil, such as, forexample, arachis oil; olive oil; sesame oil; and coconut oil; or inmineral oil, such as, for example, liquid paraffin. An oily suspensioncan also contain at least one thickening agent, such as, for example,beeswax; hard paraffin; and cetyl alcohol. In order to provide apalatable oily suspension, at least one of the sweetening agents alreadydescribed hereinabove, and/or at least one flavoring agent can be addedto the oily suspension. An oily suspension can further contain at leastone preservative, including, but not limited to, for example, anantioxidant, such as, for example, butylated hydroxyanisol, andalpha-tocopherol.

Dispersible powders and granules can, for example, be prepared byadmixing at least one compound of Formula (I) with at least onedispersing and/or wetting agent; at least one suspending agent; and/orat least one preservative. Suitable dispersing agents, wetting agents,and suspending agents are as already described above. Exemplarypreservatives include, but are not limited to, for example,anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders andgranules can also contain at least one excipient, including, but notlimited to, for example, sweetening agents; flavoring agents; andcoloring agents.

An emulsion of at least one compound of Formula (I) thereof can, forexample, be prepared as an oil-in-water emulsion. The oily phase of theemulsions comprising compounds of Formula (I) may be constituted fromknown ingredients in a known manner. The oil phase can be provided by,but is not limited to, for example, a vegetable oil, such as, forexample, olive oil and arachis oil; a mineral oil, such as, for example,liquid paraffin; and mixtures thereof. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil. Suitableemulsifying agents include, but are not limited to, for example,naturally-occurring phosphatides, e.g., soy bean lecithin; esters orpartial esters derived from fatty acids and hexitol anhydrides, such as,for example, sorbitan monooleate; and condensation products of partialesters with ethylene oxide, such as, for example, polyoxyethylenesorbitan monooleate. Preferably, a hydrophilic emulsifier is includedtogether with a lipophilic emulsifier which acts as a stabilizer. It isalso preferred to include both an oil and a fat. Together, theemulsifier(s) with or without stabilizer(s) make-up the so-calledemulsifying wax, and the wax together with the oil and fat make up theso-called emulsifying ointment base which forms the oily dispersed phaseof the cream formulations. An emulsion can also contain a sweeteningagent, a flavoring agent, a preservative, and/or an antioxidant.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

The compounds of Formula (I) can, for example, also be deliveredintravenously, subcutaneously, and/or intramuscularly via anypharmaceutically acceptable and suitable injectable form. Exemplaryinjectable forms include, but are not limited to, for example, sterileaqueous solutions comprising acceptable vehicles and solvents, such as,for example, water, Ringer's solution, and isotonic sodium chloridesolution; sterile oil-in-water microemulsions; and aqueous or oleaginoussuspensions.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e.propylene glycol) or micellar solubilization (i.e. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

A sterile injectable oil-in-water microemulsion can, for example, beprepared by 1) dissolving at least one compound of Formula (I) in anoily phase, such as, for example, a mixture of soybean oil and lecithin;2) combining the Formula (I) containing oil phase with a water andglycerol mixture; and 3) processing the combination to form amicroemulsion.

A sterile aqueous or oleaginous suspension can be prepared in accordancewith methods already known in the art. For example, a sterile aqueoussolution or suspension can be prepared with a non-toxicparenterally-acceptable diluent or solvent, such as, for example,1,3-butane diol; and a sterile oleaginous suspension can be preparedwith a sterile non-toxic acceptable solvent or suspending medium, suchas, for example, sterile fixed oils, e.g., synthetic mono- ordiglycerides; and fatty acids, such as, for example, oleic acid.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that maybe used in the pharmaceutical compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants usedin pharmaceutical dosage forms such as Tweens, polyethoxylated castoroil such as CREMOPHOR surfactant (BASF), or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin,or chemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals. The pharmaceutical compositions may be subjected toconventional pharmaceutical operations such as sterilization and/or maycontain conventional adjuvants, such as preservatives, stabilizers,wetting agents, emulsifiers, buffers etc. Tablets and pills canadditionally be prepared with enteric coatings. Such compositions mayalso comprise adjuvants, such as wetting, sweetening, flavoring, andperfuming agents.

The amounts of compounds that are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex, the medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.001 to 100 mg/kg body weight, preferably between about0.0025 and about 50 mg/kg body weight and most preferably between about0.005 to 10 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day. Other dosing schedulesinclude one dose per week and one dose per two day cycle.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered orally, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

Pharmaceutical compositions of this invention comprise at least onecompound of Formula (I) and optionally an additional agent selected fromany pharmaceutically acceptable carrier, adjuvant, and vehicle.Alternate compositions of this invention comprise a compound of theFormula (I) described herein, or a prodrug thereof, and apharmaceutically acceptable carrier, adjuvant, or vehicle.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a cardiovascular disorder, diuresis,and/or natriuresis. In another embodiment, the package insert statesthat the pharmaceutical composition can be used in combination (asdefined previously) with a second therapeutic agent to treatcardiovascular disorder, diuresis, and/or natriuresis. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, or other written sheet thatrecites information relating to the pharmaceutical composition locatedwithin the first container. The information recited will usually bedetermined by the regulatory agency governing the area in which thearticle of manufacture is to be sold (e.g., the United States Food andDrug Administration). Preferably, the package insert specificallyrecites the indications for which the pharmaceutical composition hasbeen approved. The package insert may be made of any material on which aperson can read information contained therein or thereon. Preferably,the package insert is a printable material (e.g., paper, plastic,cardboard, foil, adhesive-backed paper or plastic) on which the desiredinformation has been formed (e.g., printed or applied).

METHODS OF PREPARATION

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below.

The reactions and techniques described in this section are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used. This will sometimes requirea judgment to modify the order of the synthetic steps or to select oneparticular process scheme over another in order to obtain a desiredcompound of the invention. It will also be recognized that another majorconsideration in the planning of any synthetic route in this field isthe judicious choice of the protecting group used for protection of thereactive functional groups present in the compounds described in thisinvention. An authoritative account describing the many alternatives tothe trained practitioner is Greene et al. (Protective Groups in OrganicSynthesis, Third Edition, Wiley and Sons (1999)).

Compounds of the Formula (I) can be prepared according to the methodsoutlined in the following schemes. In Scheme 1, the thienopyridineintermediate 1.2 can be prepared from oxime 1.1 as described inUS2010/298334. Treatment of intermediate 1.2 with various alkoxides suchas sodium methoxide in solvents such as methanol can afford thecorresponding alkoxy intermediates 1.3 (R3=OCH₃, for example).Introduction of a halo group such as a bromo at the 3-position of 1.3affords 1.4 which can accomplished by treatment with N-bromosuccinimidein solvents such as DMF. The bromo group of 1.4 can be replaced with ahydroxyl group via direct treatment of 1.4 with water in the presence ofRock Phos PD G3 and cesium carbonate in solvents such as dioxaneaffording 1.5. Alternatively, 1.5 can be prepared in 2 steps from 1.4via the corresponding boronic acid 1.6. Treatment of 1.4 withbis-pinacolatodiboron in the presence of PdCl₂(dppf)-CH₂Cl₂ adduct andpotassium acetate in solvents such as dioxane affords 1.6 which can beconverted to 1.5 via treatment with hydrogen peroxide in the presence ofa base such as sodium or potassium carbonate in solvents such as THF andwater.

Coupling of the hydroxy compound 1.5 with intermediates encompassing Rgroups of the compounds of Formula I can be carried out by nucleophilicdisplacement reactions at RX, where X is tosylate, mesylate or a halidesuch as chloride or bromide. Alternatively, 1.5 can be coupled directlywith alcohols ROH via the Mitsunobu reaction affording 1.7. Treatment of1.7 with potassium carbonate and hydrogen peroxide in solvents such asDMSO affords compound of Formula I.

Certain compounds of Formula I can be prepared as outlined in Scheme 2.Displacement of the chloro group at the 2 position of compound 2.1 withan ester of mercaptoacetic acid in the presence of a base such as LiHMDSin solvents such as THF affords intermediate 2.2. Conversion of 2.2 to2.3 can be accomplished by treatment with a base such as DBU in toluene.Hydrolysis of the nitrile 2.3 to afford the primary amide 2.4 can beaccomplished with by treatment with an acid such as concentratedsulfuric acid. Compound 2.4 can be converted to 2.5 by treatment withpotassium t-butoxide in DMSO at about 80° C. Coupling of 2.5 with R¹OHor R¹X as described for Scheme 1 can provide compounds of the formula2.6. Compound 2.6 can be converted to 2.7 by nucleophilic displacementof the chloro group to afford compounds of the general Formula I.

Certain compounds of Formula I can be prepared as outlined in Scheme 3.Alkylation of the thiol 3.1 with bromoacetaldehyde diethyl acetal in thepresence of a base such as potassium carbonate in solvents such as DMFaffords 3.2 which can converted to the benzothiophene 3.3 via heating insolvents such as chlorobenzene in the presence of polyphosphoric acid.The reaction may generate a mixture of 3.3 and the correspondingregioisomeric product. Conversion of the bromo group of 3.3 to cyano togenerate 3.4 can be accomplished by treatment with zinc cyanide in thepresence of palladium tetrakis in solvents such as DMF. The nitrile 3.4can be converted to the corresponding compounds of Formula I via thesequence described for Scheme I.

EXAMPLES

Compounds of the current invention and intermediates used in thepreparation of compounds of the current invention can be prepared usingprocedures shown in the following examples and related procedures. Themethods and conditions used in these examples, and the actual compoundsprepared in these examples, are not meant to be limiting, but are meantto demonstrate how the compounds of the current invention can beprepared. Starting materials and reagents used in these examples, whennot prepared by a procedure described herein, are generally eithercommercially available, or are reported in the chemical literature, ormay be prepared by using procedures described in the chemicalliterature. The invention is further defined in the following Examples.It should be understood that the Examples are given by way ofillustration only. From the above discussion and the Examples, oneskilled in the art can ascertain the essential characteristics of theinvention, and without departing from the spirit and scope thereof, canmake various changes and modifications to adapt the invention to varioususes and conditions. As a result, the invention is not limited by theillustrative examples set forth herein below, but rather defined by theclaims appended hereto.

In the examples given, the phrase “dried and concentrated” generallyrefers to drying of a solution in an organic solvent over either sodiumsulfate or magnesium sulfate, followed by filtration and removal of thesolvent from the filtrate (generally under reduced pressure and at atemperature suitable to the stability of the material being Columnchromatography was performed with pre-packed silica gel cartridges usingan Isco medium pressure chromatography apparatus (Teledyne Corporation),eluting with the solvent or solvent mixture indicated. Preparative highperformance liquid chromatography (HPLC) was performed using a reversephase column (Waters Sunfire C₁₈, Waters Xbridge C₁₈, PHENOMENEX® AxiaC₁₈, YMC S5 ODS or the like) of a size appropriate to the quantity ofmaterial being separated, generally eluting with a gradient ofincreasing concentration of methanol or acetonitrile in water, alsocontaining 0.05% or 0.1% trifluoroacetic acid or 10 mM ammonium acetate,at a rate of elution suitable to the column size and separation to beachieved. Chemical names were determined using ChemDraw Ultra, version9.0.5 (CambridgeSoft). The following abbreviations are used:

ABBREVIATIONS

-   aq. aqueous-   brine saturated aqueous sodium chloride-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCM dichloromethane-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   DPPF 1,1′-bis(diphenylphosphino)ferrocene-   Et ethyl-   EtOAc ethyl acetate-   EtOH ethanol-   g gram(s)-   h hour(s)-   HPLC High Performance Liquid Chromatography-   LC/MS Liquid Chromatography-Mass Spectroscopy-   LiHMDS lithium bis(trimethylsilyl)amide-   MeCN acetonitrile-   MeOH methanol-   NBS N-bromosuccinimide-   PdCl₂(dppf)-CH₂Cl₂    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex    with dichloromethane-   PPA polyphosphoric acid-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran

HPLC and LC/MS Methods:

Method A: Waters Acquity UPLC BEH C18 column (2.1×50 mm), 5:95MeCN-water each with 10 mM ammonium acetate to 95:5 MeCN-water each with10 mM ammonium acetate gradient at 0.8 mL/min over 1 minute, then a 0.5min hold, 50° C. column temperature.Method B: Waters Acquity UPLC BEH C18 column (2.1×50 mm), 2:98:0.1MeCN-water-TFA to 98:2:0.1 MeCN-water-TFA gradient at 0.8 mL/min over 1minute, then a 0.5 min hold, 50° C. column temperature.Method C: Waters Acquity UPLC BEH C18 column (2.1×50 mm), 5:95:0.1MeCN-water-TFA to 95:5:0.1 MeCN-water-TFA gradient at 1 mL/min over 3minute, then a 0.75 min hold, 50° C. column temperature.

Example 13-(((2S,3S)-3-Ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide

Intermediate 1A: 5-Chlorothieno[3,2-b]pyridine-6-carbonitrile

To a solution of 1-(thiophen-3-yl)ethanone (25 g, 198 mmol) in ethanol(450 mL) and water (150 mL) was added hydroxylamine hydrochloride (27.5g, 396 mmol) followed by the addition of sodium acetate (32.5 g, 396mmol). The mixture was gently refluxed for 4 h and allowed to come toroom temperature. Ice-cold water (200 mL) was then added and the mixturewas stored at 4° C. overnight. The precipitate was collected byfiltration to afford (Z)-1-(thiophen-3-yl)ethanone oxime (26.5 g, 95%yield) as a white solid.

POCl₃ (46.5 mL, 0.499 mol) was added dropwise to a stirred solution of(Z)-1-(thiophen-3-yl)ethanone oxime (7.06 g, 0.05 mol) in ether (0.3 L)at 7-10° C. (PCT Int. Appl. 2010 13565). The mixture was stirred at7-10° C. for 2 h followed by dropwise addition of DMF (12 mL, 0.155mol). The reaction mixture was heated to distill off most of the ether,until the internal temperature gradually reached 110° C. The mixture washeated at 110° C. for an additional 1 h. Hydroxylamine hydrochloride(6.95 g, 0.100 mol) was then carefully added in small portions at ca.110° C. and the mixture was stirred for an additional 20 min period at110° C. The mixture was allowed to cool to room temperature.

The mixture was poured slowly into a stirred mixture of ice and water.The precipitated brown solid was isolated by filtration. The reactionwas repeated so that a total of 27 g of (Z)-1-(thiophen-3-yl)ethanoneoxime was consumed affording5-chlorothieno[3,2-b]pyridine-6-carbonitrile (13.5 g).

Intermediate 1B: 5-Methoxythieno[3,2-b]pyridine-6-carbonitrile

A suspension of 5-chlorothieno[3,2-b]pyridine-6-carbonitrile (1.71 g,8.79 mmol) and sodium methoxide (25% in MeOH) (2.130 mL, 9.31 mmol) inMeOH (35 mL) was stirred at 55° C. for 5.5 h. The mixture wasconcentrated, diluted with EtOAc, washed with water (2×), dried (MgSO₄),and concentrated. The crude material was triturated using hexanes toafford 5-methoxythieno[3,2-b]pyridine-6-carbonitrile (1.56 g, 93% yield)as a brown solid. ¹H NMR (400 MHz, chloroform-d) δ 8.35 (d, J=0.6 Hz,1H), 7.96 (d, J=5.5 Hz, 1H), 7.44 (dd, J=5.5, 0.6 Hz, 1H), 4.13 (s, 3H).

Intermediate 1C: 3-Bromo-5-methoxythieno[3,2-b]pyridine-6-carbonitrile

A solution of 5-methoxythieno[3,2-b]pyridine-6-carbonitrile (3.15 g,16.56 mmol) and NBS (3.54 g, 19.87 mmol) in DMF (100 mL) was stirred at60° C. for 4 h. The mixture was allowed to cool to room temperaturefollowed by the addition of water (20 mL). The solid precipitatedproduct was collected by filtration, washed with water and thetriturated with MeOH to afford3-bromo-5-methoxythieno[3,2-b]pyridine-6-carbonitrile (3.14 g, 71%yield) as a white solid. ¹H NMR (400 MHz, chloroform-d) 8.35 (s, 1H),7.95 (s, 1H), 4.21 (s, 3H).

Intermediate 1D: (6-cyano-5-methoxythieno[3,2-b]pyridin-3-yl)boronicacid

A mixture of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(49.3 g, 194 mmol),3-bromo-5-methoxythieno[3,2-b]pyridine-6-carbonitrile (47.5 g, 177mmol), potassium acetate (34.6 g, 353 mmol) and PdCl₂(dppf)-CH₂Cl₂adduct (11.53 g, 14.12 mmol) in THF (700 mL) was purged with nitrogenfor about 10 min and stirred at 60° C. overnight. LC/MS analysisrevealed that the reaction was incomplete (about 20% starting materialremained). Additional palladium catalyst (2 g) was added and thereaction mixture was stirred at 70° C. (bath temperature) for 5 h.

The mixture was cooled to 15° C. followed by the addition of an aqueoussolution (approximately 10%) of N-acetyl-L-cysteine (about 300 mL). Themixture was stirred at room temperature for 1 h. A brown solidprecipitated during this time which was isolated by filtration affordingcrude (6-cyano-5-methoxythieno[3,2-b]pyridin-3-yl)boronic acid (40 g,97% crude yield) (brown solid). LC/MS (Method A) t_(R) 0.7 min, m/z 235[M+H]+.

Intermediate 1E: 3-Hydroxy-5-methoxythieno[3,2-b]pyridine-6-carbonitrile

To a solution of sodium carbonate (3.12 g, 29.5 mmol) in water (200 mL)was added to a solution of(6-cyano-5-methoxythieno[3,2-b]pyridin-3-yl)boronic acid (2.3 g, 9.83mmol) in THF (500 mL). To the resulting clear reaction mixture was added35% hydrogen peroxide (2.87 g, 29.5 mmol) with stirring at roomtemperature. The reaction mixture was monitored by LC/MS using molecularions of the starting material and the desired product (starting materialand desired product displayed identical retention times in two separateLC/MS systems).

After stirring at room temperature for approximately 1 h, the reactionmixture was diluted with EtOAc. The organic layer was washedsequentially with semi saturated sodium thiosulfate (2×) and brine (1×).All aqueous layers were back extracted with EtOAc. The combined organicphase was dried (MgSO₄) and concentrated affording crude product. Thecrude product was subjected to flash chromatography (silica gel/DCM:MeOH100:0 to 90:10 gradient) to afford3-hydroxy-5-methoxythieno[3,2-b]pyridine-6-carbonitrile (1.55 g, 76%yield). LC/MS (Method A) t_(R) 0.7 min, m/z 207 [M+H]⁺.

Intermediate 1F:((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methylmethanesulfonate

Methanesulfonyl chloride (52.6 μL, 0.675 mmol) and TEA (111 μL, 0.798mmol) were added sequentially to a stirred solution of(4S,5S)-4-ethyl-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one (110 mg,0.614 mmol) (see ref. WO 2015/150995) in THF (0.1 mL) and DCM (0.3 mL)at −10° C., stirred for 5 min and allowed to warm to 0° C. The reactionmixture was diluted with methylene chloride and washed with saturatedsodium bicarbonate solution. The organic phase was dried (MgSO₄) andconcentrated to afford crude product. The crude product was subjected toflash chromatography (silica gel/EtOAc-MeOH 100:0 to 90:10 gradient,elutes readily) to afford((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methylmethanesulfonate (150 mg, 95% yield) as a colorless gum. ¹H NMR (400MHz, chloroform-d) δ 7.08 (br s, 1H), 4.49-4.35 (m, 1H), 4.17-3.92 (m,2H), 3.09 (s, 3H), 2.85-2.55 (m, 1H), 1.90-1.74 (m, 1H), 1.63-1.51 (m,1H), 1.13 (t, J=7.4 Hz, 3H).

Intermediate 1G:3-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carbonitrile

A mixture of ((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methylmethanesulfonate (150 mg, 0.583 mmol),3-hydroxy-5-methoxythieno[3,2-b]pyridine-6-carbonitrile (110 mg, 0.533mmol) was taken in THF (3 mL) and concentrated to dryness. The residueand anhydrous cesium carbonate (348 mg, 1.067 mmol) were taken in DMF (3mL) and heated at 90° C. for 10 min. The reaction mixture was dilutedwith EtOAc, washed with saturated sodium bicarbonate, dried (MgSO₄) andconcentrated. The crude product was subjected to flash chromatography(silica gel/hexane-EtOAc 100:0 to 0:100 gradient) to afford3-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carbonitrile(170 mg, 87% yield) as a white solid. LC/MS (Method A) t_(R) 0.88 min,m/z 368 [M+H]⁺.

Example 1

Hydrogen peroxide (35%, 135 mg, 1.388 mmol) was added to a stirredmixture of3-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carbonitrile(170 mg, 0.463 mmol) and potassium carbonate (192 mg, 1.388 mmol) inDMSO (3 mL) and stirred at room temperature for 1 h. The reactionmixture was diluted with EtOAc, washed with saturated sodiumbicarbonate, dried (MgSO₄) and concentrated. The crude product wassubjected to preparative HPLC (ODS column/water-MeOH-TFA 90:10:0.05 to10:90:0.05 gradient) to afford a white solid. The solid material wasdissolved in DCM and a few drops of MeOH and washed with saturatedNaHCO₃. The organic layer was dried (MgSO₄) and concentrated to affordthe product which was recrystallized from MeOH to afford3-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(82 mg, 46% yield) as a white solid (concentration of mother liquorafforded 40 mg of a less pure batch). LC/MS (Method A) t_(R) 0.72 min,m/z 386 [M+H]⁺. ¹H NMR (400 MHz, methanol-d₄+CDCl₃) δ 8.86 (s, 1H), 7.01(s, 1H), 4.31 (dd, J=8.8, 3.5 Hz, 1H), 4.22-4.07 (m, 5H), 2.92-2.56 (m,1H), 1.96-1.51 (m, 2H), 1.14 (t, J=7.4 Hz, 3H).

Example 23-(((2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide

Intermediate 2A:3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carbonitrile

Mesyl chloride (148 μL, 1.904 mmol) and TEA (314 μL, 2.250 mmol) wereadded sequentially to a stirred solution of(3S,4S,5S)-4-ethyl-3-fluoro-5-(hydroxymethyl) pyrrolidin-2-one (279 mg,1.731 mmol) in DCM (5 mL) at −10° C., stirred for 5 min and then allowedto warm to 0° C. The reaction mixture was diluted with DCM and washedwith saturated sodium bicarbonate solution. The organic phase was dried(MgSO₄) and concentrated to afford crude product.

The crude product and3-hydroxy-5-methoxythieno[3,2-b]pyridine-6-carbonitrile (321 mg, 1.558mmol) were taken in DMF (5 mL) followed by the addition of cesiumcarbonate (1128 mg, 3.46 mmol). The mixture was stirred at 60° C. for 2h. The reaction mixture was diluted with EtOAc, washed with saturatedsodium bicarbonate, dried (MgSO₄) and concentrated. The crude productwas subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to0:100 gradient) to afford3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carbonitrile(200 mg, 33% yield). LC/MS (Method B) t_(R) 0.86 min, m/z 350 [M+H]+.

Example 2:3-(((2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide

Hydrogen peroxide (35%, 167 mg, 1.717 mmol) was added to a stirredmixture of3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carbonitrile(200 mg, 0.572 mmol) and potassium carbonate (237 mg, 1.717 mmol) inDMSO (3 mL) and the mixture was stirred at room temperature for 1 h. Thereaction mixture was diluted with EtOAc, washed with saturated sodiumbicarbonate, dried (MgSO₄) and concentrated. The crude product waspurified by preparative HPLC (ODS column/water-MeOH-TFA 90:10:0.1 to10:90:0.1 gradient) to afford white solid. The solid material wasdissolved in DCM+a few drops of MeOH and washed with saturated NaHCO₃.The organic layer was dried (MgSO₄) and concentrated to afford theproduct which was triturated with MeOH to afford3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(125 mg, 58% yield) as a white solid. ¹H NMR (400 MHz, methanol-d₄) δ8.78 (s, 1H), 8.73-8.71 (m, 1H), 7.24 (s, 1H), 4.84 (dd, J=53.1, 5.6 Hz,1H, overlaps with water peak), 4.54-4.29 (m, 1H), 4.23-4.15 (m, 5H),2.76-2.49 (m, 1H), 1.83-1.62 (m, 2H), 1.12 (t, J=7.3 Hz, 3H). ¹⁹F NMR(376 MHz, methanol-d₄) δ −200.62 (s, 1F). LC/MS (Method B) t_(R) 0.7min, m/z 368 [M+H]⁺.

Example 3(S)-5-Methoxy-3-((5-oxopyrrolidin-2-yl)methoxy)thieno[2,3-b]pyridine-6-carboxamide

Intermediate 3A: Methyl5-chloro-6-cyano-2-((2-methoxy-2-oxoethyl)thio)nicotinate

Methyl 2,5-dichloro-6-cyanonicotinate (0.495 g) was prepared from2,5-dichloronicotinate as described in PCT Intl Appl., 2011130342.

LiHMDS (1 M in THF) (1.35 mL, 1.35 mmol) was added at 0° C. to asolution of methyl 2-mercaptoacetate (0.12 mL, 1.29 mmol) in THF (1 mL)and stirred for 5 minutes. Then, a solution of methyl2,5-dichloro-6-cyanonicotinate (0.297 g, 1.29 mmol) in THF (5 mL) wasadded and stirred at 0° C. for 30 minutes. The reaction mixture waswarmed to room temperature. The reaction was quenched with water. Themixture was diluted with EtOAc. The organic phase was washed withsaturated NH₄Cl, dried (MgSO₄), and concentrated. The crude was purifiedusing flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to0:100 gradient) to afford methyl5-chloro-6-cyano-2-((2-methoxy-2-oxoethyl)thio)nicotinate (0.258 g,66.7% yield) as a yellow solid. ¹H NMR (400 MHz, chloroform-d) δ 8.36(s, 1H), 4.00 (s, 3H), 3.88 (s, 2H), 3.80 (s, 3H).

Intermediate 3B: Methyl5-chloro-6-cyano-3-hydroxythieno[2,3-b]pyridine-2-carboxylate

A solution of methyl5-chloro-6-cyano-2-((2-methoxy-2-oxoethyl)thio)nicotinate (0.258 g, 0.86mmol) and DBU (0.142 mL, 0.94 mmol) in toluene (6 mL) was stirred atroom temperature overnight. HCl (1 N) was added and stirred for 5minutes. The mixture was extracted with EtOAc, dried (MgSO₄), andconcentrated. The crude product was purified using flash chromatography(silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient) to affordmethyl 5-chloro-6-cyano-3-hydroxythieno[2,3-b]pyridine-2-carboxylate(0.181 g, 79% yield) as an orange solid. LC MS (Method A) t_(R) 0.72,m/z 267 [M−H]. ¹H NMR (400 MHz, chloroform-d) δ 10.08 (s, 1H), 8.35 (s,1H), 4.02 (s, 3H).

Intermediate 3C: Methyl6-carbamoyl-5-chloro-3-hydroxythieno[2,3-b]pyridine-2-carboxylate

A solution of methyl5-chloro-6-cyano-3-hydroxythieno[2,3-b]pyridine-2-carboxylate (0.602 g,2.24 mmol) in sulfuric acid (3 mL, 56.3 mmol) was stirred at 60° C. for2 hours, cooled to 0° C. followed by the addition of 1N HCl. Theresulting precipitated solid was collected by filtration and washed withwater to afford methyl6-carbamoyl-5-chloro-3-hydroxythieno[2,3-b]pyridine-2-carboxylate (0.625g, 97% yield) as a brown solid. LC/MS (Method B) t_(R) 0.69, m/z 287[M−H]⁺.

Intermediate 3D: 5-Chloro-3-hydroxythieno[2,3-b]pyridine-6-carboxamide

To a stirred solution of potassium tert-butoxide (2.446 g, 21.8 mmol) inDMSO (15 mL) was added methyl6-carbamoyl-5-chloro-3-hydroxythieno[2,3-b]pyridine-2-carboxylate (0.625g, 2.18 mmol) at room temperature. After 30 minutes at room temperature,the reaction mixture was heated at 80° C. for 2.5 hours (BMCL 22 (2012)5031-5034). The mixture was diluted with EtOAc, washed with 1N HCl,water, dried (MgSO₄), and concentrated. The crude product was dissolvedin pyridine (10 mL) and stirred at 80° C. for 15 minutes. The mixturewas concentrated, diluted with EtOAc, washed with 1N HCl, water, dried(MgSO₄), and concentrated. The crude material was purified using flashchromatography (silica gel/hexanes-ethyl acetate-methanol 100:0:0 to0:90:10 gradient) to afford5-chloro-3-hydroxythieno[2,3-b]pyridine-6-carboxamide (0.369 g, 74%yield) as a brown solid. LC/MS (Method B) t_(R) 0.54, m/z 229 [M+H]+. ¹HNMR (400 MHz, methanol-d₄) δ 8.19 (s, 1H), 6.66 (s, 1H).

Intermediate 3E:(S)-5-Chloro-3-((5-oxopyrrolidin-2-yl)methoxy)thieno[2,3-b]pyridine-6-carboxamide

A mixture of 5-chloro-3-hydroxythieno[2,3-b]pyridine-6-carboxamide (0.1g, 0.44 mmol) (S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate(0.118 g, 0.44 mmol) and cesium carbonate (0.285 g, 0.88 mmol) in DMF (2mL) was stirred at 65° C. for 1.5 h. The mixture was cooled to roomtemperature and filtered. The crude material was purified usingpreparative HPLC (Phen. Luna Axia C18 5μ; 30×100 mm column; detection at220 nm; flow rate 40 mL/min; continuous gradient from 0% B to 100% Bover 10 min, 2 min hold at 100% B, where A=10:90:0.1 MeOH—H₂O-TFA andB=90:10:0.1 MeOH—H₂O-TFA) to afford(S)-5-chloro-3-((5-oxopyrrolidin-2-yl)methoxy)thieno[2,3-b]pyridine-6-carboxamide (21 mg, 14% yield) as a light brownsolid. LC/MS (Method B) t_(R) 0.58, m/z 326 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.42 (s, 1H), 8.12 (br. s., 1H), 8.08 (s, 1H), 7.78 (br. s.,1H), 7.10 (s, 1H), 4.22 (dd, J=9.0, 3.4 Hz, 1H), 4.03-3.90 (m, 2H),2.37-2.12 (m, 3H), 1.87-1.78 (m, 1H).

Example 3

A solution of(S)-5-chloro-3-((5-oxopyrrolidin-2-yl)methoxy)thieno[2,3-b]pyridine-6-carboxamide(12 mg, 0.04 mmol), copper(I) iodide (0.702 mg, 3.68 μmol) and sodiummethoxide (25% in MeOH) (0.13 mL, 0.55 mmol) was stirred at 65° C. for 1hour, cooled to room temperature and then filtered. The crude productwas purified using preparative HPLC (Phen. Luna Axia C18 5μ; 21.2×100 mmcolumn; detection at 220 nm; flow rate=40 mL/min; continuous gradientfrom 0% B to 100% B over 10 min+2 min hold at 100% B, where A=10:90:0.1MeOH—H₂O-TFA and B=90:10:0.1 MeOH—H₂O-TFA) to afford(S)-5-methoxy-3-((5-oxopyrrolidin-2-yl)methoxy)thieno[2,3-b]pyridine-6-carboxamide(4.1 mg, 33.3% yield) as a yellow solid. LC/MS (Method A) t_(R) 0.48,m/z 322 [M+H]⁺.

Example 4 3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxybenzo[b]thiophene-6-carboxamide

Intermediate 4A: 6-Bromo-5-methoxybenzo[b]thiophene

A mixture of 3-bromo-4-methoxythiophenol (1.08 g, 4.93 mmol),2-bromo-1,1-diethoxyethane (1.001 g, 5.08 mmol) and K₂CO₃ (0.783 g, 5.67mmol) in DMF (10 mL) was stirred at 110° C. for 7 hours. The mixture wasallowed to come to room temperature, diluted with DCM and washed with10% LiCl. The organic layer was then dried over Na₂SO₄ and concentratedto afford (3-bromo-4-methoxyphenyl)(2,2-diethoxyethyl)sulfane (1.6 g,4.77 mmol, 97% yield).

Intermediate 4B: 5-Methoxybenzo[b]thiophene-6-carbonitrile

A solution of (3-bromo-4-methoxyphenyl)(2,2-diethoxyethyl)sulfane (1.6g, 4.77 mmol) in chlorobenzene (2 mL) was added to a preheated stirredmixture of chlorobenzene (8 mL) and PPA (0.534 mL, 4.93 mmol) at 120° C.The mixture was stirred at 120° C. for 6 h, allowed to cool to roomtemperature, diluted with EtOAc, and washed with water. The organiclayer was then concentrated and crude product was subjected to flashchromatography (silica gel/hexanes-EtOAc 100:0 to 0:100 gradient) toafford a mixture of the two regioisomers (535 mg).

The above mixture, zinc cyanide (700 mg, 5.96 mmol) and palladiumtetrakis triphenylphosphine (197 mg, 0.170 mmol) were taken in DMF (9mL), purged with nitrogen and stirred at 120° C. for 3 h. The reactionmixture was diluted with EtOAc, washed with saturated NH₄Cl and brine,dried (MgSO₄) and concentrated. The crude product was subjected to flashchromatography (silica gel/hexane-EtOAc 100:0 to 30:70 gradient) toafford a more pure mixture of the two regioisomers. The material wassubjected to SFC (Cellulose-4 5 μm column/CO₂-MeOH 85:15 at 35° C.) toafford 5-methoxybenzo[b]thiophene-4-carbonitrile as the faster elutingisomer and the product 5-methoxybenzo[b]thiophene-6-carbonitrile (225mg) as the slower eluting isomer. ¹H NMR (400 MHz, chloroform-d) δ 8.09(s, 1H), 7.71-7.72 (d, 1H), 7.34 (s, 1H), 7.32-7.33 (d, J=5.2 Hz, 1H),4.01 (s, 3H).

Intermediate 4C: 3-Bromo-5-methoxybenzo[b]thiophene-6-carbonitrile

A mixture of 5-methoxybenzo[b]thiophene-6-carbonitrile (225 mg, 1.189mmol) and NBS (275 mg, 1.546 mmol) in DMF (5 mL) were stirred at 60° C.for 3 h, diluted with DCM and washed sequentially with 10% LiCl andbrine. The organic layer was then dried over Na₂SO₄, concentrated andthe residue was triturated with MeOH to afford3-bromo-5-methoxybenzo[b]thiophene-6-carbonitrile (245 mg, 7% yield). ¹HNMR (400 MHz, chloroform-d) δ 8.06 (s, 1H), 7.69 (s, 1H), 7.30 (s, 1H),4.09-4.05 (m, 4H).

Intermediate 4D: 3-Hydroxy-5-methoxybenzo[b]thiophene-6-carbonitrile

To the stirred solution of3-bromo-5-methoxybenzo[b]thiophene-6-carbonitrile (242 mg, 0.903 mmol)in 1,4-dioxane (8 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (248 mg,0.975 mmol) and potassium acetate (186 mg, 1.895 mmol). The mixture waspurged with N₂, then PdCl₂(dppf)-CH₂Cl₂ adduct (73.7 mg, 0.090 mmol) wasadded. The mixture was stirred at 60° C. for 24 h. The mixture wasdiluted with EtOAc, filtered through celite and the filtrated wasconcentrated. The residue was stirred with mercaptopropyl bound silicain THF (5 mL) at 40° C. for 24 h. The mixture was filtered throughcelite. The filtrate was then treated sequentially with sodiumbicarbonate (379 mg, 4.51 mmol) in water (3 mL) and 35% hydrogenperoxide (0.138 mL). The reaction mixture was stirred at roomtemperature for 45 min, diluted with EtOAc and washed with water andbrine. The organic layer was then dried over Na₂SO₄, concentrated andthe residue was subjected to flash chromatography (silicagel/hexane-EtOAc 100:0 to 0:100 gradient) to afford3-hydroxy-5-methoxybenzo[b]thiophene-6-carbonitrile (10 mg, 0.049 mmol,5.4% yield).

Example 4

A mixture of ((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methyl4-methylbenzenesulfonate (24.43 mg, 0.077 mmol),3-hydroxy-5-methoxybenzo[b]thiophene-6-carbonitrile (15 mg, 0.073 mmol)and Cs₂CO₃ (50 mg, 0.153 mmol) in DMF (2 mL) was stirred at 60° C. for 5hours. The reaction mixture was diluted with EtOAc and washed with 10%LiCl. The organic layer was dried over Na₂SO₄ and then concentrated. Theresidue was dissolved into DMSO (1.5 mL). K₂CO₃ (25.3 mg, 0.183 mmol)and 35% hydrogen peroxide (0.112 mL, 1.096 mmol) were added. The mixturewas allowed to stir at 48° C. for 12 h. The mixture was filtered and thefiltrate was subjected to preparative HPLC (C18column/water-acetonitrile with 10 mM ammonium acetate 90:10 to 10:90gradient) to afford3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxybenzo[b]thiophene-6-carboxamide(4.2 mg). LC/MS (Method C) t_(R) 1.19, m/z 367 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.86 (br s, 1H), 8.24 (s, 1H), 7.77 (br s, 1H), 7.55 (br s,1H), 7.46 (s, 1H), 6.98 (s, 1H), 4.87 (dd, J=53.4, 5.5 Hz, 1H),4.23-4.15 (m, 1H), 4.04 (br s, 1H), 3.93 (s, 3H), 3.52 (br d, J=7.6 Hz,1H), 1.72-1.48 (m, 2H), 1.00 (br t, J=7.6 Hz, 3H).

The Examples in Table 1 were prepared using the methods outlined forExamples 1-4 using the appropriate starting materials.

TABLE 1 Ex. HPLC R_(T) HPLC No. Structure (min) cond. LCMS 5

0.57 Method B 322.0 6

1.09 Method C 350.0 7

  racemic 0.91 Method C 338.0 8

1.15 Method C 368.0 9

1.15 Method C 348.0 10

1.01 Method C 350.0 11

0.86 Method C 340.0 12

0.64 Method B 372.0 13

  Diastereomer 1 0.91 Method C 336.0 14

  Diastereomer 2 0.90 Method C 336.0 15

  Diastereomer 1 1.22 Method C 350.0 16

  Diastereomer 2 1.26 Method C 350.0 17

0.98 Method C 336.0 18

0.73 Method B 380.0 19

1.38 Method C 364.0 20

1.43 Method C 376.0 21

1.13 Method C 372.0 22

1.31 Method C 382.0 23

1.36 Method C 396.0 24

1.30 Method C 394.0 25

1.00 Method C 336.0 26

0.68 Method C 352.0 27

0.67 Method B 354.0 28

0.66 Method B 354.0 29

1.13 Method C 349.0

BIOLOGICAL ASSAYS

The pharmacological properties of the compounds of this invention may beconfirmed by a number of biological assays. The exemplified biologicalassays, which follow, have been carried out with compounds of theinvention.

IRAK4 Inhibition Assay

The assays were performed in U-bottom 384-well plates. The final assayvolume was 30 μL prepared from 15 μL additions of enzyme and substrates(fluoresceinated peptide and ATP) and test compounds in assay buffer (20mM HEPES pH 7.2, 10 mM MgCl₂, 0.015% Brij 35 and 4 mM DTT). The reactionwas initiated by the combination of IRAK4 with substrates and testcompounds. The reaction mixture was incubated at room temperature for 60min. and terminated by adding 45 μL of 35 mM EDTA to each sample. Thereaction mixture was analyzed on the Caliper LABCHIP® 3000 (Caliper,Hopkinton, Mass.) by electrophoretic separation of the fluorescentsubstrate and phosphorylated product. Inhibition data were calculated bycomparison to no enzyme control reactions for 100% inhibition andvehicle-only reactions for 0% inhibition. The final concentrations ofreagents in the assays are ATP, 500 μM; FL-IPTSPITTTYFFFKKK peptide 1.5μM; IRAK4, 0.6 nM; and DMSO, 1.6%.

Caco-2 Permeability Assay

Thirteen to 27 days prior to assay, Caco-2 cells were seeded ontocollagen-coated polycarbonate filter membranes in 24-well transwellplates at a density of 1.45×10⁵ cells/cm², approximately 4.8×10⁴ cellsper well. The cells were grown in a culture medium consisting of DMEMsupplemented with 10% fetal bovine serum, 10 mM HEPES, 1% nonessentialamino acids, 2 mM L-glutamine, 100 U/mL penicillin-G, and 100 μg/mLstreptomycin. The culture medium was replaced every 3 days and the cellswere maintained at 37° C. in a 95% relative humidity and 5% CO₂atmosphere. The cells were evaluated for tight junction formation justprior to assay. The test compound was solubilized to 10 mM in 100% DMSOand diluted to 3 μM in assay buffer. Permeability studies were initiatedby adding 200 μL assay buffer plus/minus compound to the apicaltranswell compartment and 600 μL assay buffer plus/minus compound to thebasolateral compartment of the 24-well transwell low-binding clusterplate. For apical-to-basolateral (A to B) permeability (absorptivedirection), buffer containing compound was placed in the apicalcompartment (donorwells), while buffer alone was placed in thecorresponding basolateral compartments (receiverwells). Forbasolateral-to-apical (B to A) permeability (secretive direction),buffer containing compound was placed in the basolateral compartment(donor wells), while buffer alone was placed in the corresponding apicalcompartments (receiver wells). Transwells were then incubated for 2hours at 37° C. in a 95% relative humidity and 5% CO₂ atmosphere withgentle agitation. Following incubation, 100 μL was removed from eachapical and basolateral compartment and transferred to 96-well lowbinding plates that had been previously loaded with 100 μL/well ofacetonitrile containing 250 nM propranolol, 250 nM diclofenac, and 500nM tolbutamide as internal standards. The samples were subsequentlyanalyzed by LC-MS/MS to determine concentrations of compound.

IRAK4 Whole Blood Assay

Human whole blood containing the anti-coagulant ACD-A was plated in384-well plate (25 μL/well) and incubated with compounds for 60 minutesat 37° C. in a 5% CO₂ incubator. The blood was stimulated with a TLR2agonist, 10 μg/mL final concentration of lipoteichoic acid (Invivogen,San Diego, Calif.) in 25 μL RPMI (Gibco) for 5 hours in a 5% CO₂incubator. At the end of the incubation, plates were centrifuged at 2300rpm for 5 minutes. Supernatants were harvested and analyzed for IL-6levels by Flow Cytometry beads assay (BD Biosciences, San Jose, Calif.).

PBMC TLR2 Induced IL-6 Assay.

Peripheral blood mononuclear cells (PBMCs) were isolated from humanblood containing the anti-coagulant EDTA (2.5 mM) by centrifugation overa Ficoll gradient. PBMCs (250000 cells/well) were cultured in assaymedia (RPMI with 10% heat inactivated FCS) with compounds for 30 minutesat 37° C. in a 5% CO₂ incubator. Following pretreatment with compounds,cells were stimulated for 5 hours with 10 μg/mL lipoteichoic acid(Invivogen, San Diego, Calif.), a TLR2 agonist. At the end of theculture, plates were centrifuged at 1800 rpm for 10 minutes to pelletthe cells. Supernatants were harvested and analyzed for IL-6 levels byELISA (BD Biosciences, San Jose, Calif.).

The table below lists the IRAK4 IC₅₀ values, the Whole Blood EC₅₀values, and Caco-2 Permeability values for the following examples ofthis invention measured in the IRAK4 Inhibition Assay, IRAK4 Whole BloodAssay and the Caco-2 Permeability assay.

The compounds of the present invention, as exemplified by the followingexamples, showed IRAK IC₅₀ inhibition values of less than 0.6 μM.

TABLE 2 IRAK4 Inhibition Data IRAK4 Whole Blood Caco-2 Ex. No. IC₅₀ (μM)EC₅₀ (μM) Permeability (nm/s) 1 0.0006 0.058 102 2 0.0012 0.205 73 30.5578 — — 4 0.0004 0.153 85 5 0.0203 2.007 — 6 0.0010 3.211 81 7 0.6151— — 8 0.0007 0.092 42 9 0.1296 — — 10 0.5953 — — 11 0.0040 0.473 — 120.0025 0.261 — 13 0.0362 — — 14 0.4593 — — 15 0.0634 — — 16 0.0981 — —17 0.0060 0.893 — 18 0.0028 0.962 — 19 0.0106 3.299 225 20 0.0191 0.473— 21 0.0013 0.127 136 22 0.0336 — — 23 0.0014 0.189 184 24 0.0202 >10 —25 0.1279 — — 26 0.0068 — 35 27 0.0011 0.058 59 28 0.0133 0.736 58 290.0009 0.363 —

1. A compound of Formula (I)

or a salt thereof, wherein: X is CR₄ or N; Y is CR₅ or N; provided thatonly one of X and Y is N; R₁ is:

each R_(1a) is independently H, —OH, F, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆ cycloalkyl; or two R_(1a) alongwith the carbon atom to which they are attached, can form a 3- to4-membered spirocycloalkyl ring; each R_(1b) is independently H, —OH, F,C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or C₃₋₆cycloalkyl; or two R_(1b) along with the carbon atom to which they areattached, can form a 3- to 4-membered spirocycloalkyl ring; each R_(1c)is independently H, —OH, F, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy,C₁₋₃ fluoroalkoxy, or C₃₋₆ cycloalkyl; or two R_(1c) along with thecarbon atom to which they are attached, can form a 3- to 4-memberedspirocycloalkyl ring; R_(1a) and R_(1b) along with the carbon atoms towhich they are attached, can form a 3- to 4-membered cycloalkyl ring;R_(1b) and R_(1c) along with the carbon atoms to which they areattached, can form a 3- to 4-membered cycloalkyl ring; R₂ is H, halo,C₁₋₃ alkyl, or C₃₋₆ cycloalkyl; R₃ is C₁₋₄ alkoxy, C₁₋₄ fluoroalkoxy, orC₃₋₆ cycloalkoxy; R₄ is H, halo, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆cycloalkyl; and R₅ is H, halo, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆cycloalkyl.
 2. The compound according to claim 1 or a salt thereof,wherein: each R_(1a) is independently H, —OH, F, C₁₋₃ alkyl, C₁₋₂fluoroalkyl, C₁₋₂ alkoxy, C₁₋₂ fluoroalkoxy, or C₃₋₆ cycloalkyl; or twoR_(1a) along with the carbon atom to which they are attached, can form a3- to 4-membered spirocycloalkyl ring; each R_(1b) is independently H,—OH, F, C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ alkoxy, C₁₋₂ fluoroalkoxy, orC₃₋₆ cycloalkyl; or two R_(1b) along with the carbon atom to which theyare attached, can form a 3- to 4-membered spirocycloalkyl ring; eachR_(1c) is independently H, F, C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, or C₃₋₆cycloalkyl; or two R_(1c) along with the carbon atom to which they areattached, can form a 3- to 4-membered spirocycloalkyl ring; R₂ is H, F,Cl, C₁₋₂ alkyl, or C₃₋₆ cycloalkyl; R₃ is C₁₋₃ alkoxy, C₁₋₂fluoroalkoxy, or C₃₋₆ cycloalkoxy; R₄ is H, halo, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, or C₃₋₆ cycloalkyl; and R₅ is H, halo, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, or C₃₋₆ cycloalkyl.
 3. The compound according to claim 1 ora salt thereof, wherein: X is CH; Y is N; each R_(1a) is independently Hor C₁₋₂ alkyl; each R_(1b) is independently H, F, —CH₃, —CHF₂, orcyclopropyl; or two R_(1b) along with the carbon atom to which they areattached, can form a 3-membered spirocycloalkyl ring; each R_(1c) is H;R₂ is H or —CH₃; R₃ is —OCH₃, —OCH(CH₃)₂, or —O(cyclopropyl); R₄ is H;and R⁵ is H.
 4. The compound according to claim 1 or a salt thereof,wherein: R₁ is:


5. The compound according to claim 1 or a salt thereof, wherein: eachR_(1a) is independently H or C₁₋₂ alkyl; and each R_(1b) isindependently H, F, —CH₃, —CHF₂, or cyclopropyl; or two R_(1b) alongwith the carbon atom to which they are attached form a 3-memberedspirocycloalkyl ring.
 6. The compound according to claim 1 or a saltthereof, wherein: R₁ is


7. The compound according to claim 1 or a salt or prodrug thereof,wherein: each R_(1a) is independently H or C₁₋₂ alkyl; each R_(1b) isindependently H, F, —CH₃, —CHF₂, or cyclopropyl; and each R_(1c) is H.8. The compound according to claim 1 or a salt thereof, wherein saidcompound is selected from:3-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(1);3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(2);(S)-5-methoxy-3-((5-oxopyrrolidin-2-yl)methoxy)thieno[2,3-b]pyridine-6-carboxamide(3);3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxybenzo[b]thiophene-6-carboxamide(4);(S)-5-methoxy-3-((5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(5);3-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(6);5-methoxy-3-((5-oxomorpholin-3-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(7); 3-(((2 S,3S,4R)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(8);3-(((6S,7R)-7-ethyl-4-oxo-5-azaspiro[2.4]heptan-6-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(9); 3-(((2S,3R)-3-ethyl-4,4-dimethyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide (10);3-(((2S,4R)-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(11);3-(((2S,3R)-3-(difluoromethyl)-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(12); 5-methoxy-3-(((2S)-4-methyl-5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide (13-14);3-(((2S)-4-ethyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(15-16);5-methoxy-3-(((2S,3R)-3-methyl-5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(17);3-(((2S,3S,4R)-3-cyclopropyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(18);3-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxy-2-methylthieno[3,2-b]pyridine-6-carboxamide(19);5-cyclopropoxy-3-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(20);3-(((2S,3S)-4,4-difluoro-3-methyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(21);3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-methoxy-2-methylthieno[3,2-b]pyridine-6-carboxamide(22);3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-5-isopropoxythieno[3,2-b]pyridine-6-carboxamide(23);5-cyclopropoxy-3-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(24);(S)-5-methoxy-2-methyl-3-(5-oxopyrrolidin-2-yl)methoxy)thieno[3,2-b]pyridine-6-carboxamide(25);3-(((4R,5S)-5-ethyl-2-oxooxazolidin-4-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(26); 3-(((2 S,3S,4R)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(27);3-(((2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxythieno[3,2-b]pyridine-6-carboxamide(28); and3-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-5-methoxybenzo[b]thiophene-6-carboxamide(29).
 9. A pharmaceutical composition comprising one or more compoundsaccording to claim 1 and a pharmaceutically acceptable carrier ordiluent.
 10. (canceled)
 11. (canceled)
 12. (canceled)
 13. A method oftreating a disease, comprising administering to a patient atherapeutically-effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein the disease is aninflammatory or autoimmune disease selected from Crohn's disease,ulcerative colitis, Graves' disease, rheumatoid arthritis, systemiclupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis,systemic onset juvenile idiopathic arthritis, multiple sclerosis, gout,and gouty arthritis.
 14. A compound having the structure:

or a salt thereof.
 15. The compound according to claim
 14. 16. Thecompound according to claim 14, wherein said compound is a salt.
 17. Apharmaceutical composition comprising a compound according to claim 14or a pharmaceutically-acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 18. A method of treating a disease, comprisingadministering to a patient a therapeutically-effective amount of acompound according to claim 14 or a pharmaceutically acceptable saltthereof, wherein the disease is an inflammatory or autoimmune diseaseselected from Crohn's disease, ulcerative colitis, Graves' disease,rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis,cutaneous lupus, psoriasis, systemic onset juvenile idiopathicarthritis, multiple sclerosis, gout, and gouty arthritis.
 19. A compoundhaving the structure:

or a salt thereof.
 20. The compound according to claim
 19. 21. Thecompound according to claim 19, wherein said compound is a salt.
 22. Apharmaceutical composition comprising a compound according to claim 19or a pharmaceutically-acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 23. A method of treating a disease, comprisingadministering to a patient a therapeutically-effective amount of acompound according to claim 19 or a pharmaceutically acceptable saltthereof, wherein the disease is an inflammatory or autoimmune diseaseselected from Crohn's disease, ulcerative colitis, Graves' disease,rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis,cutaneous lupus, psoriasis, systemic onset juvenile idiopathicarthritis, multiple sclerosis, gout, and gouty arthritis.
 24. A compoundhaving the structure:

or a salt thereof.
 25. The compound according to claim
 24. 26. Thecompound according to claim 24, wherein said compound is a salt.
 27. Apharmaceutical composition comprising a compound according to claim 24or a pharmaceutically-acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 28. A method of treating a disease, comprisingadministering to a patient a therapeutically-effective amount of acompound according to claim 24 or a pharmaceutically acceptable saltthereof, wherein the disease is an inflammatory or autoimmune diseaseselected from Crohn's disease, ulcerative colitis, Graves' disease,rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis,cutaneous lupus, psoriasis, systemic onset juvenile idiopathicarthritis, multiple sclerosis, gout, and gouty arthritis.